Behavioral and in vivo electrophysiological evidence for presymptomatic alteration of prefrontostriatal processing in the transgenic rat model for huntington disease

J Neurosci. 2011 Jun 15;31(24):8986-97. doi: 10.1523/JNEUROSCI.1238-11.2011.

Abstract

Cognitive decline precedes motor symptoms in Huntington disease (HD). A transgenic rat model for HD carrying only 51 CAG repeats recapitulates the late-onset HD phenotype. Here, we assessed prefrontostriatal function in this model through both behavioral and electrophysiological assays. Behavioral examination consisted in a temporal bisection task within a supra-second range (2 vs.8 s), which is thought to involve prefrontostriatal networks. In two independent experiments, the behavioral analysis revealed poorer temporal sensitivity as early as 4 months of age, well before detection of overt motor deficits. At a later symptomatic age, animals were impaired in their temporal discriminative behavior. In vivo recording of field potentials in the dorsomedial striatum evoked by stimulation of the prelimbic cortex were studied in 4- to 5-month-old rats. Input/output curves, paired-pulse function, and plasticity induced by theta-burst stimulation (TBS) were assessed. Results showed an altered plasticity, with higher paired-pulse facilitation, enhanced short-term depression, as well as stronger long-term potentiation after TBS in homozygous transgenic rats. Results from the heterozygous animals mostly fell between wild-type and homozygous transgenic rats. Our results suggest that normal plasticity in prefrontostriatal circuits may be necessary for reliable and precise timing behavior. Furthermore, the present study provides the first behavioral and electrophysiological evidence of a presymptomatic alteration of prefrontostriatal processing in an animal model for Huntington disease and suggests that supra-second timing may be the earliest cognitive dysfunction in HD.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acoustic Stimulation / adverse effects
  • Age Factors
  • Analysis of Variance
  • Animals
  • Animals, Genetically Modified
  • Behavior, Animal / physiology*
  • Corpus Striatum / physiopathology*
  • Discrimination, Psychological / drug effects
  • Discrimination, Psychological / physiology
  • Disease Models, Animal
  • Electric Stimulation / methods
  • Electroencephalography / methods
  • Excitatory Amino Acid Antagonists / pharmacology
  • GABA Antagonists / pharmacology
  • Genotype
  • Huntingtin Protein
  • Huntington Disease / genetics
  • Huntington Disease / pathology*
  • Huntington Disease / physiopathology*
  • Inhibition, Psychological
  • Longitudinal Studies
  • Male
  • Nerve Tissue Proteins / genetics
  • Neural Pathways / drug effects
  • Neural Pathways / physiopathology
  • Neuropsychological Tests
  • Nuclear Proteins / genetics
  • Picrotoxin / pharmacology
  • Prefrontal Cortex / drug effects
  • Prefrontal Cortex / physiopathology*
  • Psychomotor Performance / physiology
  • Quinoxalines / pharmacology
  • Rats
  • Rats, Sprague-Dawley
  • Reaction Time / genetics
  • Reflex, Startle / drug effects
  • Reflex, Startle / genetics
  • Synaptic Membranes / drug effects
  • Synaptic Membranes / genetics
  • Synaptic Membranes / physiology*
  • Trinucleotide Repeat Expansion / genetics

Substances

  • Excitatory Amino Acid Antagonists
  • GABA Antagonists
  • Htt protein, rat
  • Huntingtin Protein
  • Nerve Tissue Proteins
  • Nuclear Proteins
  • Quinoxalines
  • Picrotoxin
  • FG 9041